Compositions and dosage forms for gasteric delivery of antineoplastic agents and methods of treatment that use them to inhibit cancer cell proliferation

ABSTRACT

The present invention provides oral dosage forms and compositions for administering antineoplastic agents, such as irinotecan, etoposide, paclitaxel, doxorubicin and vincristine, whose oral effectiveness is limited by pre-systemic and systemic deactivation in the GI tract. Gelling of the gastric retention vehicle composition, and in the case of solid forms concomitant expansion of the composition, retains the antineoplastic drug in the patient&#39;s stomach, minimizing pre-systemic and/or systemic deactivation of the drug.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of provisional application Ser. No.60/273,428, filed Mar. 5, 2001 and is a continuation-in-part of U.S.patent application Ser. No. 09/887,204, filed Jun. 22, 2001, which inturn claims priority of provisional application Ser. No. 60/213,832,filed Jun. 23, 2000, all of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to antineoplastic agents and in particularto antineoplastic agents whose oral effectiveness is limited bypre-systemic and systemic deactivation. The present invention furtherrelates to orally administered gastric delivery systems for releasingantineoplastic agents in the stomach of a patient.

BACKGROUND OF THE INVENTION

In cancer chemotherapy it is necessary to eradicate all tumor cells orthe surviving cells will continue to replicate unchecked and the cancerwill return. Toxic side effects of antineoplastic drugs impose a ceilingupon the intensity of dosing per treatment cycle. Each cycle in aprogram of treatment kills less than 99% of tumor cells and someregrowth of cancer cells occurs between cycles. The proportion of tumorcells killed in a treatment cycle typically remains constant throughoutthe program even when the disease responds well to the chemotherapy. Itis therefore indicated in cancer chemotherapy to use the highest dose ofan antineoplastic agent that a patient is able to tolerate and toadminister the drug as frequently as possible. Goodman & Gilman's ThePharmacological Basis of Therapeutics 1230 (9th ed. 1996).

Many antineoplastic agents used in cancer chemotherapy are administereddirectly to the patient's bloodstream in order to bypass problems ofabsorption and pre-systemic metabolism. Intravenous delivery is notamenable to self administration in a home setting and usuallynecessitates hospitalization at least as an outpatient. Intraveneousdosing schedules, although of high intensity, are typically lessfrequent than they would be if the drug could be administered in a homesetting by means other than intravenous injection. Chemotherapy withmany antineoplastic agents could benefit from a higher frequency dosingschedule for better efficacy, in some cases in conjunction with lowerdosing in order to reduce adverse effects.

Irinotecan (CPT-11) is an example of a drug that is currentlyadministered by i.v. for which extended duration of therapy is moreefficacious than higher dose intermittent therapy. Thompson, J. et. al.“Efficacy of oral irinotecan against neuroblastoma xenografts”Anti-Cancer Drugs (1997), 8, 313-332; Drengler, R. L. et. al., “Phase Iand Pharmacokinetic Trial of Oral Irinotecan Administered Daily for 5Days Every 3 Weeks in Patients with Solid Tumors”, Journal of ClinicalOncology (1999), 17, 685-696; Zamboni, W. C. et. al. “Studies of theEfficacy and Pharmacology of Irinotecan Against Human Colon TumorXenograft Models” Clin. Cancer Res. (1998), 4, 743-753.

Irinotecan is a water-soluble camptothecin derivative that interruptsDNA replication by binding to the topoisomerase I enzyme responsible forcutting and religating single DNA strands. Irinotecan is most effectiveagainst a particular tumor cell during the DNA synthesis phase of cellreplication, making it a phase sensitive drug. Only a fraction of tumorcells are vulnerable to cell death during a treatment cycle withirinotecan because only a fraction will be caught in the susceptiblephases of replication.

It has been shown in an animal model that lower dose dailyadministration of irinotecan is as effective and less toxic than lessfrequent higher dose administration. Houghton, P. J. et. al. “Efficacyof Topoisomerase I Inhibitors Topotecan and Irinotecan Administered atLow Dose Levels in Protracted Schedules to Mice Bearing Xenografts ofHuman Tumors” Cancer Chemother. Pharmacol. (1995), 36, 393-403;Thompson, J. et. al. “Efficacy of Systemic Administration of IrinotecanAgainst Neuroblastoma Xenografts” Clin. Cancer Res. (1997), 3, 423-432.

The greater efficacy of extended duration therapy and the reducedtoxicity of lower dose daily administration make irinotecan an excellentcandidate for oral delivery as a convenient way of achieving lower doseprotracted schedules. Rothenberg, M. L. et. al. “Alternative DosingSchedules for Irinotecan”, Oncology (1998), 8 suppl 6, 68-71.

Oral delivery, with the convenience of self administration and homedosing, would ease the burden on the patient and care giver imposed by amore frequent dosing schedule. However, the oral bioavailability ofirinotecan is reported to be only about 20% of its i.v. bioavailability.Kuhn, J. G., Ibid; Drengler, R. L., Ibid. Serious problems of absorptionand pre-systemic metabolism of irinotecan need to be overcome beforeoral delivery becomes available as a treatment option.

Irinotecan is a metabolic precursor of 7-ethyl-10-hydroxycamptothecin.The metabolite is also known by the designation SN-38. SN-38 has beenfound to be approximately a thousand times more potent an inhibitor oftopoisomerase I than irinotecan. SN-38 is formed by hydrolysis of theester side chain of irinotecan by carboxylesterases in the body.Steward, C. F. et. al., “Disposition of Irinotecan and Sn-38 FollowingOral and Intravenous Irinotecan Dosing in Mice” Cancer Chemother.Pharmacol. (1997), 40, 259-265; Kuhn, J. G., “Pharmacology ofIrinotecan” Oncology (1998), 12 supp. 6, 39-42. While the main site ofmetabolism of irinotecan to the more active SN-38 is the liver, there isconsiderable activity of carboxylesterase in the upper GI tract. Kuhn,J. G. Ibid; Takamura, K. et. al., “Involvement of Beta-glucuronidase inIntestinal Microflora in the Intestinal Toxicity of the Anti TumorCamptothecin Derivative Irinotecan Hydrochloride (CPT-11) in Rats”Cancer Res. (1996), 56, 3752-3757.

Both irinotecan and SN-38 can exist in a closed ring lactone form and anopen, hydroxy acid form. Only the lactone form of either compound isactive against tumors. Steward, C. F. et. al. Ibid; Drengler, R. L. et.al. Ibid. Acidic conditions favor the lactone form of the drug. Basicconditions favor the hydroxy acid form.

If irinotecan can be released in the stomach, the low gastric pH willkeep more of the irinotecan in the active lactone form. Therefore, moreof the SN-38 that is produced by carboxylesterases in the gut should bein the active lactone form. Steward, C. F. et. al. Ibid; Drengler, R. L.et. al. Ibid. This assumption of a higher ratio of active SN-38 toinactive SN-38 by oral delivery has been borne out in animal models andin a human phase I study. Zamboni, W. C. et. al. Ibid; Kuhn J. G. Ibid;Drengler, R. L. et. al. Ibid. Delivery and absorption of the irinotecanpreferentially in the stomach should improve its oral systemicbioavailability against tumor cells by increasing the proportion ofSN-38 that reaches the tumor in active form.

Other cell cycle specific drugs are likely to benefit from more frequentdosing which extends the duration of drug presentation to the tumor andcatches more of the cells in the sensitive phase of their cycle. Thebenefit can be realized whether they be of the topoisomerase mechanismor other phase sensitive mechanism (e.g. paclitaxel which works bystabilizing microtubule polymerization). Etoposide and paclitaxel aretwo other phase sensitive antineoplastic agents that could be used moreefficaciously with frequent lower oral dosing as opposed to intermittenthigher dosing by i.v. Etoposide binds to topoisomerase II and DNAresulting in double stranded DNA breaks that a cell cannot repair.Etoposide undergoes highly variable absorption when administered orallyand exhibits on average about 50% of its i.v. potency. Goodman & Gilman's The Pharmacological Basis of Therapeutics 1262 (9th ed. 1996).Paclitaxel is not currently administered orally.

One of the factors that causes the low oral bioavailability of etoposideand paclitaxel is removal by the P-glycoprotein (“Pgp”) efflux pumpmechanism of cells at the site of intestinal absorption. Lo, Y. L.;Huang, J. D., “Comparison of Effect of Natural or Artificial Rodent Dieton Etoposide Absorption in Rats” In Vivo (1999), 13, 51-55; Britten, C.D. et. al., “Oral Paclitaxel and Concurrent Cyclosporin A: TargetingClinically Relevant Systemic Exposure to Paclitaxel” Clin. Cancer Res.(2000), 6, 3459-3468; Fromm, M. F., “P-glycoprotein: a Defense MechanismLimiting Oral Bioavailability and CNS Accumulation of Drugs” Int. J.Clin. Pharmacol. Ther. (2000), 38, 69-74; Terwogt, J. M. M., et. al.“Co-administration of Oral Cyclosporin a Enables Oral Therapy withPaclitaxel” Clin Cancer Res (1999), 5, 3379-3384; Sparreboom, A. et. al.“Limited Oral Bioavailability and Active Epithelial Excretion ofPaclitaxel (Taxol) Caused by P-glycoprotein in the Intestine” PNAS(1997), 94, 2031-2035.

Pgp efflux pump activity is also relevant to other antineoplastic agentssuch as doxorubicin and vincristine and to anti-HIV drugs. Lum, B. L.;Gosland, M. P., “MDR Expression in Normal Tissues: PharmacologicImplications for the Clinical Use of P-glycoprotein Inhibitors” HematolOncol. Clin. North Am. (1995), 9, 319-336; Aungst, B. J.“P-glycoprotein, Secretory Transport, and Other Barriers to the OralDelivery of Anti-hiv Drugs” Adv. Drug Deliv. Rev. (1999), 39, 105-116.

Research is underway to develop new agents that are not susceptible top-glycoprotein efflux and to develop agents that inhibit the Pgp effluxpump. Morseman, J. M.; McLeod, H. L., “Taxane Chemotherapy and NewMicrotubule-Interactive Agents” Curr. Opin. Oncol. Endro. Metab. Invest.Drugs (2000), 2, 305-311; Polizzi, D. et. al., “Oral Efficacy andBioavailability of a Novel Taxane” Clin. Cancer Res. (2000), 6,2070-2074; Nicoletti, M. I. et. al. “IDN5109, a Taxane with OralBioavailability and Potent Antitumor Activity” Cancer Res. (2000), 60,842-846; Sikic, B. I., Ibid; Mistry, P., Ibid; Millward, M. J.; Lieu, E.A.; Robinson, A.; Cantwell, B. M. J., “High Dose Tamoxifen withEtoposide: a Study of a Potential Multi-drug Resistance Modulator”Oncology-Switzerland (1994), 51, 79-83; Raderer, M.; Scheithauer W.,“Clinical Trials of Agents That Reverse Multi-drug Resistance: aLiterature Review” Cancer (1993), 72, 3553-3563; Britten, C. D., Ibid;Tai, H. L., “Technology evaluation: Valspodar, Novartis AG” Curr. Opin.Mol. Ther. (2000), 2, 459-467; Terwogt, J. M. M., Ibid.

However, new agents are not a timely solution to the problem ofpre-systemic deactivation and Pgp efflux pump removal. Development andtesting of new agents, whether anti-cancer agents that are unaffected bythe efflux pump or blockers of the efflux pump, will take many yearswith unpredictable results in terms of efficacy and adverse events. Theuse of known potent efflux pump blocking agents like cyclosporin,tamoxifen, verapamil in cancer chemotherapy exposes the body to theknown potent effects of these drugs as well as their adverse eventprofiles, all as side effects of the efflux pump blocking.

If drug delivery could be used with the known effective antineoplasticagents to minimize the effects of the Pgp pump, improved oraladministration could be realized without the disadvantages describedabove and without high concomitant doses of Pgp efflux pump blockerdrugs.

Some cells that are resistant to etoposide demonstrate amplification ofthe MDR-1 gene that encodes the Pgp drug efflux transporter. Lowe et.al. Cell, 1993, 74, 957-967. The Pgp efflux pump also has been found intumor cells. Sikic, B. I., “Modulation of Multidrug Resistance: aParadigm for Translational Clinical Research” Oncology (1999) 13 A,183-189; Mistry, P. et. al. “In Vivo Efficacy of Xr9051, a PotentModulator of P-glycoprotein Mediated Multidrug Resistance” Br. J. Cancer(1999) 79, 1672-1678; Naito, M.; Tsuro, T., “Therapeutic Approach toDrug Resistant Tumors” Ther Drug Monit (1998), 20, 577-580.

However, Pgp expression was consistently found to be low in the stomachcells of five mammalian species. Beaulieu, E; Demeule, M.; Jette, L.;Beliveau, R., “Comparative Assessment of P-glycoprotein Expression inMammalian Tissues by Immunoblotting” Int. J. Bio Chromatog (1999), 4,253-269. Oral administration and absorption of etoposide, paclitaxel,doxorubicin and vincristine preferentially in the stomach should improvetheir systemic bioavailability.

Cancer chemotherapy with antineoplastic agents whose oral effectivenessis limited by pre-systemic and systemic deactivation or removal wouldgreatly benefit if the antineoplastic agent could be administered orallyand then released in the patient's stomach so that it would be absorbedpredominantly from the patient's stomach, jejunum or duodenum.

Pharmaceutical formulation specialists have developed techniques forretaining drugs in a patient's stomach over time. One of the generaltechniques is intragastric expansion, wherein expansion of the dosageform prevents it from passing through the pylorus. The diameter of thepylorus varies between individuals from about 1 to about 4 cm, averagingabout 2 cm. An expanding gastric retention dosage form must expand to atleast 2 cm×2 cm in two dimensions to cause gastric retention, though asize of 2.5 cm×2 cm is more desirable.

One type of intragastric expanding dosage form uses hydrogels to expandthe dosage form upon contact with gastric fluid to sufficient size toprevent its passage through the pylorus. An example of such a dosageform is described in U.S. Pat. No. 4,434,153. The '153 patent disclosesa device for executing a therapeutic program after oral ingestion, thedevice having a matrix formed of a non-hydrated hydrogel and a pluralityof tiny pills containing a drug dispersed throughout the matrix.

One of the major problems with intragastric expanding hydrogels is thatit can take several hours for the hydrogel to become fully hydrated andto expand to sufficient size to cause it to be retained in the stomach.Hwang, S. et al. “Gastric Retentive Drug-Delivery Systems,” CriticalReviews in Therapeutic Drug Carrier Systems, 1998, 15, 243-284 Sincenon-expanding dosage forms remain in the stomach on average for about 1to 3 hours, there is a high probability that known expanding dosageforms like that of the '153 patent will pass through the pylorus beforeattaining a sufficient size to obstruct passage. The rate-limitingfactor in the expansion of ordinary hydrogels is the rate of diffusionof water to non-surfacial hydrogel material in the dosage form.Conventional hydrogels are not very porous when they are dry, sotransport of water into the hydrogel can be slow. In addition, a lowpermeability gelatinous layer forms on the surface of wetted hydrogel,which further slows transport of water into the hydrogel.

One approach to solving the problem of slow expansion has been thedevelopment of superporous hydrogels. Superporous hydrogels havenetworks of pores of 100 μm diameter or more. At that diameter, thepores are able to rapidly transport water deep into the superporoushydrogel by capillary action. Water reaches the non-surfacial hydrogelmaterial quickly resulting in a rapid expansion of the superporoushydrogel to its full extent. Superporous hydrogels are still underdevelopment and have not been approved for pharmaceutical use by theU.S. Food and Drug Administration. There are also shortcomings attendantto the use of superporous hydrogels. They tend to be structurally weakand some are unable to withstand the mechanical stresses of the naturalcontractions that propel food out of the stomach and into the intestine.The superporous hydrogels tend to break up quickly into particles toosmall to be retained.

Chen, J. and Park, K. Journal of Controlled Release 2000, 65, 73-82,describes a superporous hydrogel whose mechanical strength is improvedby the polymerization of precursor hydrogel monomers in the presence ofseveral superdisintegrants. The result of the polymerization describedby Chen and Park is a substance having interconnecting cross-linkingnetworks of polyacrylate and, e.g., cross-linked carboxymethyl cellulosesodium. Such interconnecting networks are not expected to have the samephysical properties as conventional hydrogels made from the sameprecursor hydrogel monomers.

Another general strategy for retaining dosage forms in the stomach isintragastric floatation, as exemplified in U.S. Pat. Nos. 4,140,755 and4,167,558. Intragastric floatation systems are less dense than gastricfluid and avoid passage through the pylorus by floating on top of thegastric fluid. These systems generally take one of three forms.Hydrodynamically balanced floating systems comprise capsules of theactive ingredient and a hydrogel that forms a gelatinous coating uponcontact with water that slows further uptake of water. In one example ofsuch a system, a capsule containing the non-hydrated hydrogel and anactive ingredient dissolves upon contact with gastric fluid. Thehydrogel then comes into contact with gastric fluid and forms agelatinous coating on the surface. The gelatinous coating traps airinside the hydrogel thereby making the mass buoyant. Expansion of thehydrogel also makes it less dense and therefore more buoyant. Anotherform of intragastric floatation system is a gas generating system, whichevolves gas upon contact with water. Gas bubbles trapped in the dosageform make it buoyant. Another variation on the intragastric floatationsystems are low density core systems, wherein the active ingredient iscoated over a low density material like puffed rice.

The floating dosage forms and expanding dosage forms previouslydescribed operate by different gastric retention mechanisms, each withits own requirements to be effective. A floatation system must remainbuoyant even while absorbing gastric fluid. An expanding system mustexpand rapidly to a size sufficient to obstruct transit into theintestine and yet be small enough in its non-hydrated state to beswallowed.

The present invention includes dosage forms for gastric delivery ofantineoplastic agents in embodiments wherein the dosage form expands aswell as in embodiments wherein the dosage form expands and generates gasfor floatation.

SUMMARY OF THE INVENTION

Delivery to and absorption through parts of the gastrointestinal (GI)tract that have less activity for detrimental pre-systemic metabolism orless activity of the Pgp efflux pump will enhance the oralbioavailability of antineoplastic agents that are (1) amenable toabsorption through the stomach, jejunum or duodenum and (2) which havepoor oral bioavailability attributable either to the Pgp efflux pump orto pre-systemic deactivation.

Irinotecan has increased oral bioavailability if delivered to thestomach, without increased side effects. Gastric release of irinotecandelivers it to the acidic environment of the stomach which isadvantageous for minimizing ring-opening of the lactone form of the drugto the inactive hydroxyacid form. A greater proportion irinotecan isthus presented to the carboxylesterase enzymes in the GI tract in activeform. A greater amount of SN-38 is produced in active form whichenhances the overall in vivo potency of irinotecan.

In its particulars, the present invention provides a solidpharmaceutical dosage form comprising, as an active ingredient, anantineoplastic agent that is capable of absorption through the lining ofthe stomach, jejunum or duodenum of a human patient and a gastricretention vehicle composition comprising a hydrogel, wherein the dosageform expands by a factor of three or more, more preferably five or more,upon contact with gastric fluid or simulated gastric fluid and whereinafter ingestion by a human patient the gastric retention vehiclecomposition expands to retain the dosage form in the stomach for aprolonged period of time, preferably three hours or more. The soliddosage form may be in the form of a tablet or capsule containing theantineoplastic agent and the gastric retention vehicle composition.

The invention further provides liquid compositions comprising, as anactive ingredient, an antineoplastic agent that is capable of absorptionthrough the lining of the stomach, jejunum or duodenum of a humanpatient and a gastric retention vehicle composition comprising a gellingagent wherein after ingestion by a human patient the gastric retentionvehicle composition precipitates or gels in the patient's stomach toretain the pharmaceutical composition in the patient's stomach for aprolonged period of time, preferably three hours or more, wherein theantineoplastic agent is released from the precipitated or gelledpharmaceutical composition into the patient's stomach over a prolongedperiod of time.

The invention also provides methods of inhibiting cell proliferation ina tumor with the dosage forms and liquid pharmaceutical compositions ofthe invention. The invention further provides unit dosages ofantineoplastic agents for treatment of neoplastic diseases with thenovel dosage forms of the invention. Such neoplastic diseases includesuch widespread life-threatening diseases as breast, testicular and lungcancer. Methods of treating these diseases by repeated oraladministration of the unit dosages are also provided.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides solid dosage forms and liquidcompositions for enhanced systemic delivery of antineoplastic agents.“Systemic delivery” means delivery of the antineoplastic agent throughthe bloodstream to a tumor in the patient's body. “Enhanced systemicdelivery” means an increase in the amount of antineoplastic agent thatreaches the tumor through the bloodstream relative to the amountdelivered by a conventional orally administered non-gastric retentiondosage form or liquid composition containing the same amount of theantineoplastic agent. Enhancement in systemic delivery generallycorrelates with increased availability of the agent and/or an activemetabolite thereof in the patient's blood (bioavailability).

The term “gastric fluid” means the endogenous fluid medium of thestomach, including water and secretions, or simulated gastric fluid.“Simulated gastric fluid” means any fluid that is generally recognizedas providing a useful substitute for authentic gastric fluid inexperiments designed to assess the chemical or biochemical behavior ofsubstances in the stomach. One such simulated gastric fluid is USPGastric Fluid TS, without enzymes. United States Pharmacopeia andNational Formulary 24/19 p.2235 (1999). Thus, it will be understood thatthroughout this disclosure and in the claims “gastric fluid” meansauthentic gastric fluid or simulated gastric fluid.

The dosage forms and compositions of the present invention are adaptedto release the antineoplastic agent according to any of a wide varietyof immediate and controlled release profiles. As used herein “immediaterelease” means that release of the antineoplastic agent is notsignificantly delayed by means of a protective coating or embedding in amatrix. The excipients used to achieve immediate release typicallydissolve or disperse rapidly in gastric fluid. “Sustained release” meansrelease of the antineoplastic agent from the dosage form over a longerperiod of time than the immediate release time of the sameantineoplastic agent from an equivalent dosage in an immediate releaseformulation. “Delayed release” means that there is a period of timeafter the dosage form contacts gastric fluid during which theantineoplastic agent either is not released or is released at a ratethat is not therapeutically effective for the purpose that the drug hasbeen administered to the patient. “Burst release” means release of mostof the antineoplastic agent over a short period of time, typically lessthan 30 minutes. “Pulsed release” means release of the antineoplasticagent over two or more time periods separated by a period of time inwhich either the antineoplastic agent is not release or is released at arate that is not therapeutically effective for the purpose that the drughas been administered to the patient. Burst release, pulsed release andsustained release may be coupled with delayed release so that release ofthe antineoplastic agent according to that profile begins after a delayperiod in which the antineoplastic agent either is not released or isreleased at a rate that is not therapeutically effective for the purposethat the drug has been administered to the patient. The term “controlledrelease” is used inclusively to mean delayed release; sustained release,including delayed sustained release; burst release, including delayedburst release; pulsed release, including delayed pulsed release; and anyrelease other than immediate release.

The solid dosage forms and liquid compositions of the present inventioncontain a gastric retention vehicle composition (alternatively “gastricretention delivery system” or “GRDS”) and an antineoplastic agent thatis capable of being absorbed through the lining of the stomach, jejunumor duodenum of a cancer patient. The solid dosage forms of the inventionas described in their particulars below are adapted for administrationto human patients. Adjustments in dosage form size and dosage so as toadapt a solid dosage form of the invention for other mammals, which arealso patients as the term is used in this disclosure, is within theskill level of those in the art

Solid dosage forms and liquid compositions according to the presentinvention are administered to the patient orally. The antineoplasticagent is released from the dosage form in the patient's stomach. Theantineoplastic agent is then absorbed through the lining of the stomach,jejunum or duodenum and passes into the patient's bloodstream. Systemicdelivery of the antineoplastic agent to the tumor is increased by thesolid dosage forms and liquid compositions of this invention byreleasing the antineoplastic agent in the stomach, which avoidspre-systemic deactivation or degradation of the agent in the patient'slower GI tract (i.e. ileum and colon).

As used herein an “antineoplastic agent” is an agent that inhibits cellproliferation in a tumor and prodrugs, solvates, molecular complexes andpharmaceutically acceptable salts and derivatives of the agent.Antineoplastic agents that may be administered to a patient using thesolid dosage forms and liquid compositions of this invention include anyantineoplastic agent that is delivered to a tumor by means of thepatient's bloodstream and which is adversely affected by thep-glycoprotein efflux pump in the small intestine or by the pH of thesmall intestine. Such antineoplastic agents include irinotecan,etoposide, paclitaxel, doxorubicin and vincristine, especiallyirinotecan, etoposide and paclitaxel. In a particularly preferredembodiment, the antineoplastic agent is irinotecan. One reason thatirinotecan is especially preferred is that the ability of the soliddosage forms and liquid compositions of the invention to releaseirinotecan in the stomach over an extended period provides a uniquebenefit with irinotecan since a greater proportion of irinotecan isconverted into the highly active metabolite SN-38 before entering thehigh pH environment of the small intestine. This results in productionof more active-form SN-38.

The gastric retention vehicle compositions of this invention form agelatinous mass upon contact with gastric fluid. The gastric retentionvehicle compositions may be in either a solid form or a liquid form.

Preferred solid gastric retention vehicle compositions for solid dosageforms contain a hydrogel and, optionally, a superdintegrant and/ortannic. Similar compositions, wherein a superdisintegrant and tannicacid are incorporated, are described in commonly-assigned, co-pendingU.S. patent application Ser. No. 09/887,204, which is herebyincorporated by reference in its entirety.

A hydrogel is a polymeric material that can absorb more than 20% of itsweight in water while maintaining a distinct three-dimensionalstructure. In their hydrated condition they swell to an equilibriumvolume, are elastically deformable but virtually immune to plasticdeformation. In their non-hydrated state, hydrogels may be structurallyrigid. As used herein, “hydrogels” include dry polymers that swell inaqueous environments in addition to the water-swollen polymers. Thepreferred hydrogel of the gastric retention vehicle composition ishydroxypropyl methylcellulose (HPMC), either alone or in combinationwith hydroxypropyl cellulose (HPC) and/or a cross-linked acrylatepolymer. Preferably, the HPMC has a molecular weight of from about 4000to about 100,000 a.u. and a viscosity grade of about 8000 mPa·s or less.HPMC is commercially available under the trade name Methocel® from DowChemical Co.

Hydroxypropyl cellulose suitable for use in the gastric retentionvehicle composition preferably has a molecular weight in the range offrom about 80,000 to about 1.2 million, more preferably from about 1.0million to about 1.2 million. HPC is commercially available under thetrade name Klucel® from Hercules Inc.

Suitable cross-linked acrylate polymers include polyacrylic acidcrosslinked with allyl sucrose commercially available under the tradename Carbopol® (BF Goodrich Chemical Ltd.) and polyacrylic acid crosslinked with divinyl glycol.

The most preferred hydrogel of the present invention is a mixture ofHPMC and HPC in a weight ratio of from about 1:3 to about 5:3.

Other polymeric substances that absorb water may be substituted for thepreferred hydrogels of the invention. According to the teachings of U.S.Pat. No. 5,972,389 polyethylene oxide may be used as a swellablepolymer, while U.S. Pat. No. 4,434,153 discloses a wide variety of otherwater swellable polymers that also may provide acceptable substitutesfor the HPMC and HPMC/HPC mixtures that have been found best-adapted forpractice of the invention. U.S. Pat. Nos. 5,972,389 and 4,434,153 arehereby incorporated by reference in their entirety.

The solid form gastric retention vehicle composition may further includetannic acid. Tannic acid, also called tannin, gallotannin andgallotannic acid, is a naturally occurring constituent of the bark andfruit of many trees. The term “tannins” conventionally refers to twogroups of compounds, “condensed tannins” and “hydrolyzable tannins.”Merck Index monograph No. 8828 (9th ed. 1976). The hydrolyzable tanninsare sugars that are esterified with one or more (polyhydroxylarene)formic acids. One common polyhydroxylarene formic acid substituent oftannic acid is galloyl (i e. 3,4,5-trihydroxybenzoyl). Another commonpolyhydroxylarene formic acid substituent of tannic acid ismeta-digallic acid. A common sugar moiety of tannic acid is glucose.Preferably, USP grade tannic acid is used.

The gastric retention vehicle composition optionally also includes asuperdistintegrant. Superdisintegrants are disintegrants that expandupon contact with water. Preferred superdisintegrants of the presentinvention expand to at least double their non-hydrated volume on contactwith water. Exemplary of these superdisintegrants are cross-linkedcarboxymethyl cellulose sodium (a.k.a. croscarmellose sodium), sodiumstarch glycolate and cross-linked polyvinyl pyrollidone (a.k.a.crospovidone). Croscarmellose sodium is commercially available from FMCCorp. under the tradename Ac-Di-Sol® and from Avebe Corp. under thetradename Primellose®. Sodium starch glycolate is commercially availablefrom Penwest Pharmaceuticals Co. under the tradename Explotab® and fromAvebe Corp. under the tradename Primojel®. Crospovidone is commerciallyavailable from BASF Corp. under the tradename Kollidon® CL and fromInternational Specialty Chemicals Corp. under the tradenamePolyplasdone®. The most preferred superdisintegrant is sodium starchglycolate.

More preferred gastric retention vehicle compositions for use in soliddosage forms of the invention contain HPMC, optionally HPC, tannic acid,and a superdisintegrant selected from the group consisting ofcrosspovidone, croscarmellose sodium and sodium starch glycolate andmixtures thereof.

An especially preferred solid form gastric retention vehicle composition(particularly for tableting) comprises, in a weight ratio exclusive ofany other excipients that may be present, from about 20 wt. % to about70 wt. % hydrogel (e.g. HPMC or HPMC+HPC), from about 25 wt. % to about75 wt. % superdisintegrant and from about 2 wt. % to about 10 wt. %tannic acid. Within these ranges, a yet more preferred gastric retentionvehicle composition for tableting comprises from about 30 wt. % to about55 wt. % superdisintegrant, about 5 wt. % (±2 wt. %) tannic acid, plusan amount of hydrogel sufficient to bring the total to 100%.

When a mixture of HPMC and HPC is selected as the hydrogel and sodiumstarch glycolate is selected as the superdisintegrant, the gastricretention vehicle composition preferably comprises from about 10 wt. %to about 20 wt. % HPMC, from about 45 wt. % to about 50 wt. % HPC, about25 wt. % to about 35 wt. % sodium starch glycolate and about 4 wt. % toabout 10 wt. % tannic acid.

An alternative preferred gastric retention vehicle compositioncontaining HPMC, HPC further comprises croscarmellose sodium. Theformulation may comprise from about 10 wt. % to about 30 wt. % HPMC,from about 40 wt. % to about 60 wt. % HPC, about 7 wt. % to about 35 wt.% croscarmellose sodium and about 4 wt. % to about 10 wt. % tannic acid.

Having specifically described novel gastric retention vehiclecompositions that are best known compositions for use withantineoplastic agents, it is to be understood that gastric retention ofantineoplastic agents also may be achieved using other known gastricretention vehicle compositions, such as hydrogel matrix compositions asdescribed in U.S. Pat. No. 4,642,233, or multicomponent systems likethat of U.S. Pat. No. 5,780,057. U.S. Pat. Nos. 4,642,233 and 5,780,057are hereby incorporated by reference in their entirety.

Solid gastric retention dosage forms of the invention may be expandingtablets or capsules.

Expanding tablets may be prepared by compacting the gastric retentionvehicle composition, antineoplastic agent and, optionally, otherexcipients, as a powder blend or granulate in any type of tabletingequipment known to the pharmaceutical arts.

Expanding tablets may contain the antineoplastic agent dispersed in thegastric retention vehicle composition. The antineoplastic agent may bedispersed as a powder or crystals in the gastric retention vehiclecomposition or may be incorporated into beads, pills (U.S. Pat. No.4,642,233), pellets, microcapsules, microspheres, microgranules,nanocapsules or nanospheres and the like that are embedded within thegastric retention vehicle composition.

Expanding tablets may be prepared conventionally by dry blending, drygranulation or wet granulation, followed by compaction of the resultingtableting composition in a tableting machine. Granulation techniqueswill now be illustrated with an illustrative gastric retention vehiclecomposition that includes a superdisintegrant and tannic acid.

In dry granulation, the gastric retention vehicle composition is blendeddry and then compacted into a slug or a sheet and then comminuted intocompacted granules. It will be appreciated that the processes ofslugging or roller compaction, followed by comminution and recompressionrender the hydrogel, superdisintegrant and tannic acid intragranular inthe final dosage form. The antineoplastic agent may also be providedintragranularly by blending it with the gastric retention vehiclecomposition prior to compaction and comminution. Alternatively, theantineoplastic agent, hydrogel, superdisintegrant or tannic acid may beadded after comminution, which results in that (or those) ingredient(s)being extragranular. The resulting tableting composition or granulatemay be used to prepare an expanding tablet or capsule by any of themethods described below or any other means.

In wet granulation, the gastric retention vehicle composition andantineoplastic agent may be granulated using a water:alcohol mixture oran alcohol as a granulation solvent by standard granulation techniquesknown in the art. The granulate may then be dried and optionally milledand sieved. The hydrogel, superdisintegrant, tannic acid orantineoplastic agent may be added to one or more of the wet granulatedingredients either before or after compaction, in which case aningredient added after granulation would be extragranular in the finaldosage form. After drying, the tabletting composition, or granulate,prepared by wet granulation may be used to prepare an expanding tabletor capsule by any of the methods described below or any other means.

In dry blending, the hydrogel, superdisintegrant, tannic acid,antineoplastic agent and any other desired excipients are blended inpowder form prior to direct compression tableting.

The tableting composition prepared by dry granulation, wet granulationor dry blending may be compacted following conventional compression anddirect compression techniques. In direct compression, the tabletingcomposition has been dry blended. Direct compression produces a moreuniform tablet without granules. Excipients that may be added to thetableting composition which are particularly well suited for directcompression tableting include microcrystalline cellulose, spray driedlactose, dicalcium phosphate dihydrate and colloidal silica. The properuse of these and other excipients in direct compression tableting isknown to those in the art with experience and skill in the particularformulation challenges of direct compression tableting.

In some dosage forms, controlled release of the antineoplastic agent maybe provided by applying a coating to the antineoplastic agent. Thus,where the foregoing description of making tablets has described mixing,blending, granulating, compressing, etc. of the antineoplastic agent, itwill be appreciated by those skilled in the art that the antineoplasticagent may previously be coated with a coating. Coatings are discusses inmore detail below

The preceding description is intended to highlight variations offormulation techniques already well known in the art. However, theexpanding tablets of the invention can be made by any manufacturingprocess. Specific novel and therapeutically useful gastric retentiondosage forms are disclosed below.

Expanding tablets may be a matrix type in which the antineoplastic agentis contained in or coats the surface of particles uniformly dispersedthroughout the gastric retention vehicle composition. In a matrixconstruction, the particles of antineoplastic agent may be a milledpowder or granulate. The particles also may be pre-formulated beads,pills, pellets, microcapsules, microspheres, microgranules, nanocapsulesor nanospheres and the like containing or having on their surface theantineoplastic agent, in which case these pre-formulated particles aredispersed in the matrix.

A pre-formulated particle may contain the powdered antineoplastic agentin a natural, semi-synthetic or synthetic polymer matrix. Representativematrices for dispersed particles are polysaccharides, agar, agarose,sodium alginate, carrageenan, gum arabic, tragacanth gum, locust beangum, pectin, amylopectin, gelatin, starch, microcrystalline celluloseand hydrogels. Further particle matrices can include crosslinkedgelatin, crosslinked albumin, crosslinked sodium alginate, crosslinkedcarboxymethylcellulose, crosslinked polyvinyl alcohol and crosslinkedchitin as described in U.S. Pat. No. 5,007,790.

A pre-formulated particle may contain the antineoplastic agent inmixture with excipients that do not retard its release. Even if theparticle core contains excipients that in certain applications wouldretard release of an active ingredient, such as high molecular weightpolyvinyl pyrollidone, rapid release from a particle may occurnevertheless due to the small volume and relatively large surface areaof particles.

A pre-formulated particle, e.g., bead, tiny pill, microsphere,nanosphere or microgranule, may be coated with a substance or substancesthat are impermeable or semipermeable to the antineoplastic agent and/orslowly dissolve in gastric fluid. Such a coating may be used to slow therelease of the antineoplastic agent or to delay the release of theantineoplastic agent. A delay release coating is impermeable to theantineoplastic agent until the coating is breached by the gastric fluid.Dosage forms of the matrix type may be formulated for delayed releaseusing coated particles, in which case the gastric retention vehiclecomposition will retain the dosage forms in the stomach until the delaytime has passed, whereupon the drug is released.

Delayed release and sustained release particles may be coated with knownfilm coating agents such as water soluble resins, such asarabinogalactan, carboxymethylcellulose, gelatin, gum arabic,hydroxyethylcellulose, methylcellulose, polyvinyl alcohol, polyacrylicacid, and starch; water insoluble resins, such as cellulose nitrate,ethyl cellulose, e.g., Ethocel™; cellulose nitrate, polyamide,polyethylene, poly(ethylene-vinyl acetate), poly(lactide-co-glycolide),polymethacrylate, e.g., Eudragit™ NE, Eudragit™ RS, Eudragit™ RL,Eudragit™ L and Eudragit™ S and silicones; waxes and lipids such asparaffin, carnauba wax, spermaceti, beeswax, stearic acid stearylalcohol and glyceryl stearates; and enteric resins such as celluloseacetate phthalate, polyvinyl acetate and hydroxypropyl methylcelluloseacetate. The glyceryl esters may be mixed with a wax as previouslydescribed in U.S. Pat. No. 4,764,380, which is incorporated by referencein its entirety. Such a coating may be made from triglyceryl esters likeglyceryl distearate, glyceryl tristearate, glyceryl monostearate,glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monolaurate,glyceryl didocosanoate, glyceryl tridocosanoate, glycerylmonodocosanoate, glyceryl monocaprate, glyceryl dicaprate, glyceryltricaprate, glyceryl monomyristate, glyceryl dimyristate, glyceryltrimyristate, glyceryl monodecenoate, glyceryl didecenoate and glyceryltridecenoate. Waxes that may be used include beeswax, cetyl palmitate,spermacetic wax, carnauba wax, cetyl myristate, cetyl palmitate, cerylcerotate, stearyl palmitate, stearyl myristate and lauryl laurate.Particles coatings may also be from other polymeric coating substanceswhich include methylcellulose phthalate, poly(alkyl methacrylates),poly(alkyl cyanoacrylates), polyglutaraldehyde, poly(lactide-glycolide)and albumin. Additional coating materials that may be used are disclosedin U.S. Pat. Nos. 4,434,153; 4,721,613; 4,853,229; 2,996,431; 3,139,383and 4,752,470, which are hereby incorporated by reference in theirentirety.

Pre-formulated particles coated with delayed release coatings may beadvantageously used to produce an expanding tablet or capsule for pulsedrelease of the antineoplastic agent. Gastric fluid rapidly penetratesthe expanding dosage form because of the hydrophilicity and porosity ofthe preferred gastric retention vehicle compositions. Consequently, thecoated particles contact gastric fluid approximately simultaneouslyregardless of their proximity to the outer surface of the dosage form.One can deliver two, three (or more) timed doses in a pulse fashionwhile the patient needs to take the dose only once. For this purpose,particles may be provided with coatings of different thicknesses.Alternatively, the particles may be coated with different substanceshaving different dissolution rates in gastric fluid. The coatings of acertain proportion of particles, either those with a thin coating or arelatively soluble coating, are breached nearly simultaneously. Thiscauses release of the antineoplastic agents from those particles over ashort time period, i.e., in a pulse. A second pulse occurs when thecoating of particles having either a thicker coating or a coating of aslower dissolving substance is breached. A third pulse occurs whenparticles having a coating that is either yet thicker or formed of a yetless soluble substance is breached. The timing and intensity of thepulses can be determined by the formulator using knowledge availableabout the dissolution rates of coating substances and by routinelyselecting the proportion of each type of coated particle to match theintensity of the pulse desired. The three doses would mimic takingmultiple doses of the antineoplastic agent at the prescribed times, withthe antineoplastic agent being absorbed from the stomach or upperintestine with each dose. Such dosing allows for improved compliance todosage schedules and in many cases will lead to improved therapy. Pulsedrelease dosage forms that do not include gastric retention will delivereach pulse in a different part of the GI tract with different absorptionprofiles for each of the doses. Such therapy would not be equivalent totaking three doses of the antineoplastic agent at the prescribed times,wherein the antineoplastic agent would have been absorbed from thestomach or upper intestine in each case.

In a hydrated state, the gastric retention vehicle compositions of thisinvention do not necessarily limit diffusion of a solubilizedantineoplastic agent into the gastric environment. Therefore, the pulsedrelease of antineoplastic agent inside of the expanded tablet maytranslate into pulsed release into the gastric fluid.

Expanding tablets also may contain the antineoplastic agent in areservoir (or depot) adjacent to, at least partially surrounding or atleast partially surrounded by the gastric retention vehicle composition.Reservoir forms may contain the antineoplastic agent in a reservoir thatis embedded in a shell of any desired thickness that does not cause thedosage form to be too large to be swallowed by the patient. Embeddedtablets and tablets with cores are examples of reservoir type of dosageforms. A reservoir type further includes capsule forms, multilayer formsand other forms wherein the antineoplastic agent is separated from theexpanding composition. The reservoir may be fully embedded in a shell ofthe expanding composition or it may be partially embedded so that aportion of the surface of the reservoir is exposed. A reservoir may be atablet enclosed within a capsule along with a tablet containing theexpanding composition. These types of products may be manufactured usingmethods known in the art, while novel and particular preferredembodiments of reservoir dosage forms are described below.

The reservoir may be formulated to be either immediate release orcontrolled release. The release profile of the dosage form may be madeto approximate the release profile of the reservoir (even when thereservoir is completely embedded in a shell) because the hydrated andexpanded composition does not necessarily inhibit diffusion ofsolubilized substances into the gastric environment. For example, animmediate release reservoir may be prepared by blending theantineoplastic agent with microcrystalline cellulose, lactose andmagnesium stearate and compressing the blend into a compacted reservoir.For another example, a sustained release reservoir may be prepared bydirect compression of the antineoplastic agent with about 5-75%hydroxypropyl methylcellulose, such as Methocel® KI 5M, K100LV, K4M,K100M, E4M and E10M, lactose and magnesium stearate.

A reservoir may be coated with a conventional sustained release coating.Such coating materials include polymethacrylate, e.g., Eudragit™ NE,Eudragit™ RS, Eudragit™ RL, Eudragit™ L, Eudragit™ S, and mixtures ofhydrophilic and hydrophobic film forming agents. Hydrophilic filmformers include methyl cellulose, hydroxypropyl methylcellulose,cellulose phthalate, cellulose acetate phthalate and polyvinyl alcohol.Hydrophobic film forming agents include ethyl cellulose, celluloseacetate, hydroxypropyl methylcellulose phthalate, polyvinyl alcoholmaleic anhydride copolymers, β-pinene polymers rosin, partiallyhydrogenated rosin and glycerol esters of rosin. A sustained releasecoating may be applied by methods known in the art such as by fluid bedor pan coating techniques.

In addition to being of an immediate release or sustained releasenature, the reservoir can further be of a delayed pulse release natureor a delayed-sustained release nature. For instance, the antineoplasticagent may also be contained in tablets that are either partiallyembedded in the gastric retention vehicle composition or attachedthereto by an adhesive. These tablets can be of a slow release naturegiving slow or controlled release for an extended period of time in thestomach. These tablets can further be of a delayed pulse release nature.The expanding composition of this invention will retain these forms inthe stomach until the delay time has passed whereupon the drug will bereleased in a burst or pulse fashion. Attaching or partially embeddingseveral such tablets, each timed with a different delay to release, tothe composition of this invention allows versatile dosing schemes fromone taken dose. For example one could deliver three (or more) timeddoses in a pulse fashion while the patient needs to take the dose onlyonce. The three doses would mimic taking three doses of the drug at theprescribed times, with the drug being absorbed from the stomach witheach dose. Such dosing allows for improved compliance to dosageschedules and in many cases will lead thereby to improved therapy.Delayed dosage forms that are not coupled to gastric retention willdeliver each such dose in a different part of the GI tract withdifferent absorption profiles for each of the doses. Such therapy wouldnot be equivalent to taking three doses of the drug at the prescribedtimes, wherein the drug would have been absorbed from the stomach ineach case.

The reservoir may also be attached to the expanding composition with anadhesive. The gastric retention vehicle composition is compacted into atablet (“GRDS tablet,”). The reservoir can be attached by adhesiveduring manufacture by depositing a drop of adhesive on a GRDS tablet asit leaves the punch station in the tableting machine and having a devicepush the reservoir, e.g., another tablet, containing the drug againstthe deposited adhesive.

Expanding tablets may also have a layered construction wherein theantineoplastic agent, alone or in mixture with any other excipients,form a layer that is bonded, e.g., by compression, to another layercontaining the expanding composition. Preferred dimensions for a layereddosage form are about 14×8 mm±2 mm. A layered construction may beprepared by conventional multilayer compression techniques. A layereddosage form comprising two or more layers, one comprising the expandingcomposition and another comprising the antineoplastic agent and anyother desired excipients, may be made to delay release of theantineoplastic agent by coating only the antineoplastic agent-containinglayer with a conventional coating resistant to gastric fluids. A furthermethod of achieving a delay in the release is to formulate thedrug-containing layer as a matrix that delays diffusion and erosion orby incorporating the antineoplastic agent in microcapsules or coatedbeads within the drug-containing layer.

Another solid dosage form is a capsule. The capsule shell may be anyconventional shell (e.g. gelatin) that degrades in gastric fluid torelease a capsule filling. The capsule filling comprises a powder blendor granulate (as previously described) or tablet containing the gastricretention vehicle composition, antineoplastic agent and, optionally,other excipients. Capsules exhibit a similar rate and extent ofexpansion as tablets and are retained in the stomach for a comparabletime period. There is, however, a delay in the commencement of expansionfor the time required for degradation of the capsule shell to allowgastric fluid to contact the gastric retention vehicle composition.

In an especially preferred capsule embodiment, the capsule encloses atablet (or other reservoir) containing the antineoplastic agent and aGRDS tablet. The two tablets can be adhered to each other in situ thestomach by coating a side of one of the tablets that faces the othertablet with an aqueous based adhesive. The tablets are loaded into anappropriately sized gelatin capsule where the tablets are in physicalcontact. When water enters the capsule, the adhesive is wetted andadheres the tablets together due to their proximity in the capsule priorto the rapid swelling of the GRDS tablet. The tablets remain adhered toeach other after the swelling. Preferred water based adhesives for thisuse are protein adhesives such as gelatin, egg albumin, and casein,their salts and derivatives and polysaccharide adhesives such as starch,modified starches, and other polysaccharide derivatives known in the artas glues. The most preferred adhesive for in situ adhesion of the drugreservoir to a GRDS tablet is sodium caseinate, which is availablecommercially as Emulac™ 50.

Solid dosage forms of this invention may be made in any shape desired.Ovoid or elliptical shaped tablets are well retained in human patientsafter expanding to their full extent. An ovoid or elliptical dosage formpreferably is sized at between about 4 mm and 10 mm in two dimensionsand between about 10 mm and 20 mm in the third dimension, morepreferably 6×6×16 mm±2 mm.

Solid dosage forms of this invention can be retained in the stomach forthree hours or more, more preferably about five hours or more. Thedosage forms of the present invention are capable of expanding in volumeby a factor of about three or more, about five or more if an gastricretention vehicle composition according to the preferred embodiments isused and, about eight or more if an gastric retention vehiclecomposition according to the most preferred embodiments is used.Expansion occurs within about fifteen minutes of contacting gastricfluid, within about five minutes when formulated according to thepreferred embodiments. Over time, the swollen dosage form degrades intoparticles that are sufficiently small to traverse the pylorus.

Further improvement in gastric residence time may be realized by addingan effervescent compound to the gastric retention vehicle compositionthat produces gas when contacted with gastric fluid, such as sodiumbicarbonate. In a dry granulation process, the effervescent compound maybe introduced into the dosage form by blending it into the gastricretention vehicle composition before or after first compaction. In a wetgranulation process, it may be provided as an extragranular constituentafter wet granulation. Further, the effervescent compound may be aconstituent of a reservoir in reservoir-type dosage form. Theeffervescent compound is preferably used at low concentration, i.e. fromabout 0.5 wt % to about 5 wt. % of the dosage form. In addition tosodium bicarbonate, effervescent compounds include, for example, otheralkali and alkaline-earth metal carbonates and bicarbonates.

Mucoadhesive substances also may be added to enhance gastric retentionof dosage forms prepared according to the present invention.

In another aspect, the present invention provides liquid compositionsfor gastric delivery of antineoplastic agents. In the liquid formembodiments of the invention, the antineoplastic agent is dissolved ordispersed in a gastric retention vehicle composition comprising agelling agent. The liquid pharmaceutical composition may be a solution,suspension, or syrup.

The gastric retention properties of the liquid pharmaceuticalcomposition are afforded by gelling, precipitation or coacervation ofthe gelling agent in the stomach. The gel, precipitate or coacervatethat forms in the patient's stomach traps the drug in the stomach for anextended gastric delivery. The gelling agent may be activated by achange in pH or change in temperature. The gelling agent may contain asynthetic polymer, a polysaccharide, a protein or a coacervate of aprotein and a polysaccharide as a gelling agent. Examples of suchdelivery systems are known in the art but have not been suggested asbeing useful for the oral systemic delivery of antineoplastic agents.Cox, G., “Pectin Liquid Compositions,” WO 96/29055; Bogentoft, C.,“Gel-forming, Liquid Carrier Compositions, and Their Use inPharmaceutical Dosage Forms,” WO 92/09307; Zatz, J. L.; Woodford, D. W.,“Oral Controlled Release Liquid Pharmaceutical Which Forms GelatinousMatrix in the Stomach,” U.S. Pat. No. 4,717,713. U.S. Pat. No. 4,717,713and International Publications WO 96/29055 and WO 92/09307 are herebyincorporated by reference in their entirety.

A gelling agent of the liquid pharmaceutical composition may be basedupon coacervation brought about by exposure to low pH. One such systemis a mixture of ethyl hydroxyethylcellulose (EHEC) and a surfactant.

Suitable surfactants are cationic surfactants and anionic surfactantsthat do not protonate at gastric pH. Suitable surfactants includehexadecyltrimethylammonium chloride, tetradecylbetainate chloride andhexadecylpyridinium chloride, sodium dodecyl sulfate, sodium dodecylmonoethyleneoxide sulfate, sodium dodecyl sulfonate, sodium dosdecylphosphate, sodium doecyl phosphonate, sodium p-dodecylbenzene sulfonateto name just a few. Other surfactants may be used so long as they engagein a strong hydrophobic interaction with ethylhydroxyethylcellulose inaqueous solution at gastric pH.

The total concentration of a EHEC/surfactant system is preferably in therange of 0.5-3 wt. %, more preferably from about 0.5 to 1.5 wt. %. EHECis used in approximately 5 to 25 fold excess over the surfactant, byweight.

Another pH activated gelling agent is a mixture of a low methoxylatedpectin and a divalent metal salt, like calcium carbonate, that is coatedwith a substance that dissolves upon contact with acid. Release of themetal salt in the patient's stomach causes the cation to engage incrosslinking interactions with the pectin molecules so as to form agelatinous network and, in the case of carbonate salt, produces gasbubbles which are entrapped in the gelatinous network. Preferredmethoxylated pectins have 20-50% degree of methoxylation, preferablyfrom about 30-40% degree of methoxylation and a degree of amidation offrom about 3% to about 23%. This system may be used to deliverantineoplastic agents according to the present invention either with theeffervescent aspect or without the effervescent aspect by using a noneffervescent calcium salt anion such as stearyl.

The gelling agent may be activated by increased temperature.Methylcellulose forms aqueous dispersions that are flowable below bodytemperature but which become viscous with increased temperature. At bodytemperature, a dispersion of 5 wt. % or above of methylcellulose inwater forms a gel of sufficient mechanical resilience to be retained inthe stomach.

Yet other operative gelling systems include a mixture of from about 0.5to about 4 weight percent sodium alginate, 0.5 to about 3 weight percentor less of xanthan gum, carrageenan or gelatin.

In addition to the substances previously discussed which enable gastricretention, the solid and liquid form gastric retention vehiclecompositions may contain other excipients which may be added for avariety of purposes. It will be understood by those in the art that somesubstances serve more than one purpose in a pharmaceutical composition.For instance, some substances are binders that help hold a tablettogether after compression, yet are disintegrants that help break thetablet apart once it reaches a patient's stomach. It will be furtherunderstood that the hydrogel, superdisintegrant and tannic acid of themost preferred solid form gastric retention vehicle composition mayperform additional functions in the dosage form, which functions mayalready be known to those skilled in the art.

Additional excipients that may be added include diluents. Diluentsincrease the bulk of a pharmaceutical dosage form making it easier forthe patient and caregiver to handle. Diluents for solid dosage formsinclude, for example, microcrystalline cellulose (e.g. Avicel®),microfine cellulose, lactose, starch, pregelitinized starch, calciumcarbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasiccalcium phosphate dihydrate, tribasic calcium phosphate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, mannitol,polymethacrylates (e.g. Eudragit®), potassium chloride, powderedcellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted into a tablet mayinclude excipients whose functions include helping to bind the activeingredient and other excipients together after compression. Binders forsolid pharmaceutical compositions include acacia, alginic acid, carbomer(e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methylcellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate,maltodextrin, methylcellulose, polymethacrylates, povidone (e.g.Kollidon®, Plasdone®), pregelatinized starch, sodium alginate andstarch.

The dissolution rate of a compacted solid pharmaceutical composition inthe patient's stomach may be increased by the addition of a disintegrantto the composition. Disintegrants include alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g.Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellosesodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum,magnesium aluminum silicate, methyl cellulose, microcrystallinecellulose, polacrilin potassium, powdered cellulose, pregelatinizedstarch, sodium alginate, sodium starch glycolate (e.g. Explotab®) andstarch.

Glidants can be added to improve the flow properties of a powdercomposition or granulate and improve the accuracy of dosing. Excipientsthat may function as glidants include colloidal silicon dixoide,magnesium trisilicate, powdered cellulose, starch, talc and tribasiccalcium phosphate.

A tablet is made by compressing a powder composition granulate between apunch and dye. Some excipients and active ingredients have a tendancy toadhere to the surfaces of the punch and dye, which can cause the tabletto have pitting and other surface irregularities. A lubricant may beadded to the composition to reduce adhesion and ease release of theproduct form the dye. Lubricants include magnesium stearate, calciumstearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenatedcastor oil, hydrogenated vegetable oil, mineral oil, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate,stearic acid, talc and zinc stearate.

Liquid pharmaceutical compositions will contain a solvent such as cornsyrup, water, glycol, glycerin, propylene glycol, vegetable oils andalcohols.

Liquid pharmaceutical compositions may contain emulsifying agents todisperse a poorly soluble antineoplastic agent or an excipient uniformlythroughout the composition. Emulsifying agents that may be useful inliquid pharmaceutical compositions of the present invention include, forexample, lecithin, sorbitan monoleate, gelatin, egg yolk, casein,cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose,carbomer, cetostearyl alcohol and cetyl alcohol.

Liquid pharmaceutical compositions may also contain a viscosityenhancing agent to improve the mouth-feel of the product and/or coat thelining of the gastrointestinal tract. Such agents include acacia,alginic acid bentonite, carbomer, carboxymethylcellulose calcium orsodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatinguar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylenecarbonate, propylene glycol alginate, sodium alginate, sodium starchglycolate, starch tragacanth and xanthan gum.

Preservatives and chelating agents such as alcohol, sodium benzoate,butylated hydroxy toluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid may be added at levels safe for ingestion to improvestorage stability.

A liquid composition according to the present invention may also containa buffer such as guconic acid, lactic acid, citric acid or acetic acid,sodium guconate, sodium lactate, sodium citrate or sodium acetate.

Flavoring agents and flavor enhancers make the solid dosage forms andliquid pharmaceutical compositions more palatable to the patient. Commonflavoring agents and flavor enhancers for pharmaceutical products thatmay be included in the composition of the present invention includemaltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid,ethyl maltol, and tartaric acid. Sweetening agents such as sorbitol,saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol andinvert sugar may be added to improve the taste.

Solid and liquid compositions may also be dyed using anypharmaceutically acceptable colorant to improve their appearance and/orfacilitate patient identification of the product and unit dosage level.

Selection of additional excipients and the amounts to use may be readilydetermined by the formulation scientist based upon experience andconsideration of standard procedures and reference works in the field.

A unit dose of irinotecan in one of the dosage forms of the presentinvention, e.g. one tablet or capsule of a solid form or an ingestiblevolume, like a tablespoon of syrup, of a liquid form preferably is dosedwith from about 20 to about 250 mg of irinotecan, more preferably fromabout 20 to about 40 mg of irinotecan.

A unit dose of etoposide in one of the forms of the present inventionpreferably contains from about 25 to about 250 mg of etoposide, morepreferably from about 25 to about 75 mg of etoposide, and yet morepreferably from about 25 to about 50 mg.

A unit dose of paclitaxel in one of the forms of the present inventionpreferably contains from about 25 to about 250 mg of paclitaxel and morepreferably from about 25 to about 100 mg of paclitaxel.

Having thus described the present invention with reference to certainpreferred embodiments, the following non-limiting examples are providedto further illustrate the invention.

EXAMPLES

Materials

The HPMC used was Methocel® K-15PM, available from Dow Chemical Co. Thehydroxypropyl cellulose used was Klucel® HF NF; available from Hercules,except where otherwise indicated. The croscarmellose sodium used wasAc-Di-Sol® available from Avebe Corp. The crosslinked polyacrylic acidwas Carbopol® 974P available from B.F. Goodrich Chemical Ltd. TannicAcid was purchased from Merck. All materials were pharmaceutical grade.

Example 1 Degree of Swelling of Illustrative Solid Gastric RetentionDelivery Systems

The compositions of each of the tablets prepared in Example 1 aresummarized in Table 1. All the compositions contain HPMC, tannic acid, asuperdisintegrant and 1% magnesium stearate. All of the excipients,except for magnesium stearate, were mixed simultaneously and thoroughlyblended by hand. Magnesium stearate was then added at a level of 1% w/wand the blend was further mixed by hand until the magnesium stearate wasuniformly distributed throughout the composition. The amount of eachcomposition needed to produce a 5 mm thick tablet was determined andthen that amount was compressed into 5 mm thick tablets on a Manesty f3single punch tableting machine with a 10 mm diameter punch and die.Tablets ranged in weight from 350-400 mg and each had a hardness withinthe range of 5-7 KP as tested in an Erweka hardness tester. TABLE 1 GRDSFormulations for Degree of Swelling Tests Formulation No. (wt. %)Excipient 1 2 3 4 5 6 7 8 Hydroxypropyl methylcellulose 23.8 32.7 30.323.8 26.7 38.5 34.8 15.9 Hydroxypropyl cellulose 0.0 0.0 0.0 0.0 16.019.2 0.0 47.6 Cross-linked polyacrylic acid 0.0 0.0 0.0 0.0 0.0 0.0 8.70.0 Total hydrogel 23.8 32.7 30.3 23.8 42.7 57.7 43.5 63.5 Sodium starchglycolate 71.4 65.4 60.6 0.0 53.3 38.5 52.2 31.7 Croscarmellose sodium0.0 0.0 0.0 71.4 0.0 0.0 0.0 0.0 Tannic acid 4.8 2.0 9.1 4.8 4.0 3.8 4.34.8 Total 100 100 100 100 100 100 100 100

The tablets were added to 40 ml of simulated gastric fluid (0.1 M HCl)contained in a 50 ml beaker and maintained at 37±2° C. The tablets wereremoved after fifteen minutes with a tweezers and measured with acaliper. Gel strength was assessed qualitatively with the tweezers.

The results of the degree of swelling tests are summarized in Table 2.Expansion, of the hydrogel was increased using either croscarmellosesodium or sodium starch glycolate. The formulation can optionally andadvantageously contain a mixture of two hydrogel polymers asdemonstrated by the incorporation hydroxypropyl cellulose and Carbopol®in the formulations of Examples 5, 6 and 8. The tablet that expanded themost (36 fold) contained about 5 wt. % tannic acid and croscarmellosesodium as the superdisintegrant. The tablet with the second highestexpansion (18 fold) also contained about 5 wt. % tannic acid but usedsodium starch glycolate as the superdisintegrant. Both of those gels(Examples 1 and 4) were qualitatively weak compared to those of examples5-8. The best performing tablets in terms of a high degree of expansionand good mechanical strength are those of Examples 5 and 8, whichcontained 5 wt. % tannic acid and used both hydroxypropylmethylcellulose and hydroxypropyl cellulose hydrogel polymers. TABLE 2Formulation Degree of No. Swelling^(a) Strength 1 18.1 moderate 2 12.7moderate 3 7.2 moderate 4 36.0 moderate 5 10.4 strong 6 2.0 strong 7 4.5strong 8 9.7 strong^(a)ratio of hydrated tablet volume to dry tablet volume

Example 2 Rate of Swelling of Illustrative Solid Gastric RetentionVehicle Compositions

The formulations in Table 3, below, were prepared by first dry mixingthe powdered ingredients, except the magnesium stearate, for 5 minutes.Magnesium stearate was then added and blended in over 2 minutes. Theformulation was pressed into oval tablets of dimensions 17×9×8.5 mmusing a Manesty f3 single punch tablet press where the 8.5 is the tabletthickness or height in the dimension of compression. TABLE 3 GRDSFormulations for Rate of Swelling Tests Formulation No. (wt. %)Ingredient 10 11 12 HPMC K15 16 15.7 13.4 HPC 48 47.2 45 Croscarmellosesodium 31.9 31.4 29.1 Tannic acid 3.1 4.7 12 Magnesium stearate 1 1 0.5

The tablets were immersed in 450 ml of USP Gastric TS buffer (pH=1.2)without enzymes at 37° C. in a USP type II dissolution bath with thepaddles set at the top of the buffer so as not to hit the expandingtablets. The solution was stirred at 50 RPM. The tablets were removedfrom the buffer at 15 minutes, 1 and 3 hours, gently blotted dry withpaper, and measured using a calibrated caliper. The two majordimensions, length and height, were measured. The third dimensionexpanded from 9 mm to about 14 mm in all of the cases. Results of themeasurements are shown in Table 4. TABLE 4 Rate and Degreee of Swellingof GRDS tablets in USP Gastric TS buffer Formulation No.: 10 11 12 Time(hours) Size (mm × mm) Size (mm × mm) Size (mm × mm) 0  17 × 8.5  17 ×8.5  17 × 8.5 0.25 21 × 15 25 × 21 25 × 18 1 21 × 15 32 × 24 27 × 19 321 × 15 32 × 24 27 × 20

Most of the expansion occurred in the first 15 minutes. One can see thatthe degree of expansion was greatest in the dimension of compression.This dimension expanded between 1.8 and 2.8 times its size. In length,the tablet grew from 1.2 to 1.9 times its size.

Example 3 Effect of GRDS Composition on Gel Strength

Method

Gel strength was measured by the weight needed to deflect the expandedgel by 4 mm. The gels were removed from the Gastric TS buffer, blotteddry with paper, and placed on a flat surface on a top loading balance. Aplastic cylinder was placed on the gel and water was added slowly to thecylinder until the gel was compressed downward by 4 mm. The weightrequired for 4 mm deflection was recorded.

Effect of Tannic Acid Content on Gel Strength

Formulations were prepared as in Example 2 with varying amounts oftannic acid. Tablets were pressed and immersed in simulated gastricfluid as described in Example 2. All the tablets swelled to at least25×22 mm in 15 minutes. Results of the measurement of gel strength arefound in Table 5. TABLE 5 Strength of Expanded Gels as a Function ofTannic Acid Content Formulation % Tannic Acid Strength (g) 13 4.2 27 144.7 51 15 6 90 16 7 147

Raising the percent of tannic acid from 4.2 to 7 percent dramaticallyincreased the strength the expanded gel. In experiments not reported inTable 5 it was discovered that increasing the percent of tannic acidfrom 7 and 12% resulted in little further increase in gel strength.

Effect of Superdisintegrant Content on Gel Strength

Formulations were prepared as described in Example 2 with varyingamounts of croscarmellose sodium. Tablets were pressed and the tabletswere immersed in simulated gastric fluid as described in Example 2. Allthe tablets swelled to at least 23×18 mm in 15 minutes. The formulationstested and the results of the measurement of gel strength are providedin Table 6. TABLE 6 Strength of Expanded Gels as a Function ofCroscarmellose Sodium Content Formulation No. (wt. %) Ingredient 17 1819 HPC 46.6 50 55.9 Croscarmellose sodium 31 26 21.4 HPMC K15 15.5 1515.7 Tannic acid 5.9 6 6 Magnesium stearate 1 1 1 Weight required todeflect 90 116 157 gel by 4 mm (g)

As can be seen in Table 6, lowering the percent of the superdisintegrantin the formulation tended to increase the gel strength.

Example 4 Gastric Retention Delivery System with In Situ External TabletAdhesion

One method of obtaining pulsed delivery of a drug in the stomach is toattach tablets with predetermined delays before disintegration to thegastric retention delivery system (GRDS) tablet. Such attachment can bethrough partial embedding of the tablet in the GRDS matrix or byadhering it externally to the GRDS. In this example we show thefeasibility of such external adhesion.

The GRDS formulation was that shown in Table 7. TABLE 7 IngredientWeight Percent HPC 50.3 HPMC 16.7 Croscarmellose Sodium 22 Tannic Acid10.0 Magnesium Stearate 1.0

The powders, except the lubricant, were mixed for five minutes.Magnesium stearate was then added and the powders mixed for one minutemore. The blend was pressed into rectangular (truncated oval) tablets of10×7×7 mm in a Manesty f3 single punch tableting machine.

An adhesive solution was prepared as follows. Sodium caseinate (Emolac™50, 15 g) was dissolved in 100 ml water by stirring overnight at roomtemperature. 500 ml of ethanol was added with stirring to obtain anemulsion of 2.5% sodium caseinate in water:ethanol.

The tablets were then coated with the adhesive. The emulsion was spraycoated on the tablets in a pan coater at a rate of 4 ml/min with theproduct temperature between 30-40° C. to a coating weight of between 5and 14 mg. The tablets were air dried in the coating pan to give GRDStablets coated with the adhesive.

Placebo tablets based on microcrystalline cellulose were prepared (5×5×5mm rectangular) and coated with Eudragit™ S to make them impervious toacid conditions. The tablets were loaded into a gelatin #00 capsule in astack such that a GRDS tablet was in between two placebo tablets. Thecontact between the tablets was on the 7×7 mm face of the GRDS tabletwhich is perpendicular to the compression axis.

The gelatin capsules were placed in 0.1 N HCl in a USP type IIdissolution bath at 37° C. and stirred at 50 RPM. The capsule dissolvedand the three tablet stack adhered to one another in situ. Within 15minutes the GRDS tablet had swollen to 13×22 mm from 10×7 mm (theswelling being mostly along the compression axis). At two hours the GRDStablet had swollen to 14×25 mm. The placebo tablets remained attached tothe GRDS tablet, despite its swelling, for over 12 hours in thedissolution bath. In order to test the viability of the adherence undermore vigorous conditions of flow, the stack was placed in 0.1 N HCl at37° C. in a disintegration tester at 50 strokes per minute. The flows onthe tablets in a disintegration tester are considerably stronger than inthe dissolution tester. The three tablets remained adhered to oneanother for 10 hours.

Example 5 Solid Dosage Forms for Gastric Delivery of AntineoplasticAgents

An antineoplastic agent can be formulated with the GRDS system inseveral ways. It can be dispersed homogeneously throughout theformulation. It can be formulated into a separate tablet that isembedded into the GRDS matrix. It can be formulated as a separate layerand a bilayer GRDS formed. Irinotecan is delivered by controlled releasein each of the formulations below while the GRDS portion has swelledgreatly to afford gastric retention. Each form has its advantages. Thedispersed tablet has the advantage of ease of manufacture. It, however,has less flexibility in formulative control over the rate of releasesince most of the excipients in the matrix are dictated by its GRDSnature. The embedded tablet and the bilayer tablet are somewhat morecomplicated to form, necessitating special commercial equipment for bothembedding tablets and for bilayer tablets, but they offer the advantageof full freedom in formulating the drug layer, thereby allowing agreater measure of control for the drug release profile.

1) Irinotecan Dispersed Homogeneously Throughout the GRDS

Tablets containing irinotecan were made by direct compression. Theformulations made are given in Table 8. All the components except themagnesium stearate were blended manually for three minutes. Magnesiumstearate was added and the blend mixed for a further minute. The blendwas then pressed into 850 mg tablets in a Korsch 6 punch press usingoval punches of dimension 16×8 mm. TABLE 8 Formulations of IrinotecanHomogeneously Dispersed in a GRDS Matrix Formulation No. (wt. %)Ingredient 20 21 22 Irinotecan 7.1 7.1 7.1 HPC HF 55.6 47.6 49.8Croscarmellose sodium 11.5 23.1 17.3 HPMC K15M 15.9 13.6 15.9 TannicAcid 9.4 8.1 9.4 Magnesium Stearate 0.5 0.5 0.5

The tablets were tested for swelling and gel strength as described abovein Example 2. The tablets were further tested for drug release insimulated gastric test solution in a USP type II dissolution bath at 37°C. with a paddle speed of 50 RPM. The results of these tests are givenin Table 9. TABLE 9 Swelling and Dissolution of Irinotecan in DispersedGRDS Tablets Time Formulation No. Characteristic (hr) 20 21 22Dimensions 1 21.3 × 14.4 31.1 × 28.0 28.4 × 26.3 (length × height) (mm)3 22.9 × 16.3 30.9 × 29.1 29.0 × 26.7 6 23.8 × 19.0 32.1 × 29.1 28.9 ×28.3 Water uptake 1 1.4 8.9 7.6 (g) 3 2.3 9.6 7.7 6 3 9.6 7.7 GelStrength (g) 1 1188 105 106 3 801 101 161 6 554 101 193 Percent Release2 0 18 7 of Irinotecan 4 1 31 11 6 2 43 16 8 4 54 20

2) Irinotecan in a Tablet Partially Embedded in the GRDS

Irinotecan and the excipients in Table 10 were granulated with water,dried and milled. Magnesium Stearate (0.5%) was added and the blendmixed for one minute. Tablets of diameter 6 mm weighing 85 mg wereproduced in a Korsch 6 punch rotary tablet machine. The formulationstested are given in Table 10. TABLE 10 Formulations of Inner IrinotecanTablet Formulation No. (wt. %) Ingredient 23 24 Irinotecan 70 70 Lactose25 0 Mannitol 0 20 HPMC K100LV 5 10

These core tablets were coated with a thin coat (˜10μ) layer of EudragitE, a methacrylate polymer that is readily soluble in acidicenvironments. The core tablets were then embedded at the surface of aGRDS matrix tablet whose composition is shown in Table 11. TABLE 11 GRDSComposition of Formulations Nos. 23 and 24 Ingredient Weight PercentCroscarmellose sodium 22.0 HPC HF 50.3 HPMC K15M 16.7 Tannic Acid 10.0Magnesium stearate 1.0

The tablets expanded readily in gastric TS solution with a water uptakeof at least 6 grams. These tablets were tested for drug release asdescribed above. The results are given in Table 12. TABLE 12 CumulativePercent Release of Drug from Embedded Tablets Percent Release Time (hr)23 24 0 0 0 1 6 3 2 14 7 4 63 27 8 87 73

3) Irinotecan as a Separate Layer—Bilayer GRDS

Irinotecan was granulated with about 10% of the HPMC and half themannitol using water as the granulation liquid. After drying andmilling, the granulate was blended with the croscarmellose sodium, theremaining HPMC and mannitol and subsequently with the magnesium stearatefor a final formulation as shown in Table 13. TABLE 13 Composition ofIrinotecan-Containing Layer of Bilayer Tablet Ingredient Weight PercentIrinotecan 30 HPMC K100LV 27 Mannitol 23 Croscarmellose sodium 20Magnesium stearate 0.3

The GRDS layer was made by blending the following ingredients: TABLE 14Composition of GRDS Layer of Bilayer Tablet Ingredient Weight PercentCroscarmellose sodium 20 HPC HF 52 HPMC K15M 17 Tannic Acid 10 MagnesiumStearate 1

The GRDS blend, 800 mg, was fed into the die of a 16×8 mm oval punch.The irinotecan blend, 200 mg, was added as a separate layer over theGRDS blend. The entire assembly was pressed into a bilayer tablet. Thetablets showed proper swelling properties and were tested for drugrelease in a USP type II dissolution apparatus as described above. Theresults of the drug release are shown in Table 15. TABLE 15 CumulativePercent Release of Drug from Bilayer Tablets Time (h) Percent Release 00 1 33 2 49 4 85 8 98

Example 6 Enhanced Systemic Delivery of Irinotecan and SN-38 by GastricAbsorption of Irinotecan in the Beagle Dog

Introduction

Six dogs are used in a 3 way crossover study to determine the area underthe curve (“AUC”) of bloodstream concentration versus time after oraladministration of irinotecan in a GRDS tablet and after an i.v. dosingof the drug. Blood samples are taken at predetermined intervals and theconcentration of irinotecan lactone, irinotecan carboxylate, SN-38lactone and SN-38 carboxylate are determined by HPLC methods. SN-38 isthe active metabolite of irinotecan and only the lactone form is active.A plot of plasma concentration against time allows calculation of thearea under the curves and the relative bioavailability of the variousforms of the drug. Enhancement in the percentage of the lactone form ofSN-38 when dosing orally with a GRDS formulation makes oral dosing aviable alternative to i.v. dosing.

Blood Sampling for Pharmacokinetic Evaluation

Prior to the study, an adequate amount (5-10 ml) of whole blood is drawnfrom each dog. The blood is used to prepare the standard calibrationreference curve. At the study, the foreleg (right or left, as deemedappropriate by the animal handler), is shaved using an electric shaver,and the area cleansed with a chlorhexidine swab. A permanent in-dwellingpolyethylene catheter is inserted using a 23 gauge needle in thecephalic vein in the foreleg of each dog and taped in place to allow forperiodic blood sampling over 12 hours. A plastic bonnet is placed aroundthe head of each dog to ensure that the dog's mouth cannot reach thecatheter site.

At each time point, 2.0 ml blood is removed by syringe and then placedinto a pre-labeled heparinized test tube. The test-tube is immediatelycentrifuged and extracted with cold methanol to prevent equilibrationbetween the lactone and the carboxylate forms of the two drugs after theblood has been drawn. The concentration of the components are measuredusing literature HPLC methods. See Drengler, R. L. et. al., “Phase I andPharmacokinetic Trial of Oral Irinotecan Administered Daily for 5 DaysEvery 3 Weeks in Patients with Solid Tumors”, Journal of ClinicalOncology (1999), 17, 685-696.

The Study

The dogs are fasted overnight for a period of at least 12 hours at whichtime they receive a single mixed meal of solid food and liquidnutrients. 250 grams of bite-size commercial dog chow (Bonzo Feed®) aremeasured and placed in a feeding dish. The dog is allowed to eat over ½hour, at which time the dish is removed. The food remaining in the dishis measured and the difference from the original 250 grams is recordedas the amount of food consumed. Additionally, 250 calories of liquidnutrients (Ensure®, 237 ml) are administered via a gastroesophagealfeeding tube. No additional food is allowed for the duration of thestudy, but water is provided ad libitum from a tap in the dog's cageduring the study.

Prior to dosing, the dog is prepared for catheter insertion and a“pre-dosing” “0” hour blood sample is drawn. The blood is drawn and thesample handled as described above.

Two hours after the meal, the dog is dosed with the test tablet. Afteradministering the test tablet, 300 ml of pH regulated (pH 2.0) water isadministered by flexible tubing to the stomach. Every hour followingdosing, up to 12 hours, a sample (2 ml) of whole blood is withdrawn fromthe catheter and placed in a heparinized glass test-tube. The bloodsamples are centrifuged immediately and extracted with cold methanol.The methanol samples are analyzed by HPLC.

Results

The following ratios may be derived from the HPLC results of tests inwhich irinotecan is administered orally in a gastric retention dosageform and in which the drug is administered intravenously.$\frac{A_{lactone}^{GR}}{A_{Total}^{GR}},{\frac{A_{Total}^{GR}}{A_{Total}^{IV}}\quad{and}\quad{\frac{A_{Total}^{IV}}{A_{lactone}^{IV}}.}}$

Quantity “A” is the total area under the bloodstream concentration curveover time. Superscript “GR” refers to results of a test in whichirinotecan was administered in a gastric retention dosage form accordingto the invention and superscript “IV” refers to results of a test inwhich irinotecan was administered intravenously. Superscript “Oral” isused below to refer to results of a test in which irinotecan wasadministered in a conventional, non-gastric retention dosage form.

A_(Total)=A_(Lactone)+A_(Carboxylate) is the sum of the areas under thecurve of lactone and carboxylate forms of the species.

These ratios are useful for calculating the relative bioavailability ofactive form irinotecan and SN-38 by different routes of administration.The literature contains data on the bioavailability achieved byconventional oral administration and by intravenous administration, fromwhich the relative bioavailability of irinotecan and its activemetabolite by conventional oral administration and intravenousadministration can be calculated, as shown in Table 16. TABLE 16Relative Oral, Non-Gastric Retention Bioavailability of Irinotecan andSN-38 Derived from Literature m = Irinotecan m = SN-38$\left\lbrack \frac{A_{Total}^{Oral}}{A_{Total}^{IV}} \right\rbrack_{m}$0.12 0.16$\left\lbrack \frac{A_{Lactone}^{Oral}}{A_{Total}^{Oral}} \right\rbrack_{m}$0.35 0.73$\left\lbrack \frac{A_{Lactone}^{IV}}{A_{Total}^{IV}} \right\rbrack_{m}$0.35 0.50 $\begin{matrix}{{Calculated}\quad{Relative}\quad{Bioavailability}\quad{of}} \\{{Lactone}\quad\left\lbrack {A_{Lactone}^{Oral}/A_{Lactone}^{IV}} \right\rbrack}_{m}\end{matrix}\quad$ 0.12 0.22Drengler, R. L. et. al., “Phase I and Pharmacokinetic Trial of OralIrinotecan Administered Daily for 5 Days Every 3 Weeks in Patients withSolid Tumors”, Journal of Clinical Oncology (1999), 17, 685-696.

As can be seen, the relative bioavailability of both the irinotecan andSN-38 lactones when irinotecan is administered orally is less than 25%of their bioavailability when irinotecan is administered intravenously.

It will be seen that gastric delivery of irinotecan greatly increasesthe bioavailability of the metabolite. By increasing the ratio of SN-38that is adsorbed in the lactone form ([A_(Lactone) ^(GR)/A_(Total)^(GR)]_(SN-38)) from 0.73 to 0.9 and increasing overall delivery ofSN-38 to the bloodstream ([A_(lactone) ^(GR)/A_(Total) ^(IV)]_(SN-38))from 0.16 to 0.4 through retention of the irinotecan in the absorbingregion of the GI tract, one achieves more than half the intravenousbioavailability of SN-38. In fact, one achieves a bioavailability ofSN-38 of 0.7 relative to its intravenous bioavailability. Improvement inthe absorption of irinotecan and the proportion that is absorbed inlactone form is also achieved (e.g. 0.12->0.2 and 0.35->0.5,respectively). Since SN-38 is a thousand times more potent thanirinotecan, an increase in degree of SN-38 absorption and the proportionof SN-38 absorbed in the lactone form are significant results caused bygastric retention.

Such improvement makes gastric oral delivery of irinotecan a viableoption compared to i.v. delivery and, actually, an improved option inlight of the greater effectiveness of more sustained low doseadministration of irinotecan over less frequent high dose treatment.Embodiments of the gastric retention dosage forms of this invention areadapted for sustained, delay and pulsed release (and combinationsthereof) Moreover, the ability to administer them orally in a homesetting permits increased dosage frequency without inconvenience to thepatient or caregiver.

Example 7 Liquid Formulation of Paclitaxel for Gastric Delivery

Introduction

Oral dosing of paclitaxel is limited by paclitaxel's insolubility and byits active exclusion from intestinal absorption by P-glycoprotein pumpsthat cause drug resistance. Paclitaxel can be formulated in a solubleform by complexing it with human serum albumin (WO 99/13914) obtaining asolution of 1 mg/ml paclitaxel. Oral dosing of this formulation will notlead to a greatly improved bioavailability because the Pgp pumps arestill preventing the absorption of the drug. Gastric delivery of theformulation should allow its oral delivery by forcing the drug to beabsorbed mostly in the stomach and thus avoiding the areas of maximumPgp pump activity.

Methods

Three rabbits weighing 2.5 kg each are used in a 3 way crossover studyto determine the AUC of bloodstream concentration of paclitaxel versustime after oral administration of a gastric retention liquid formulationof paclitaxel-albumin complex according to the invention and an aqueoussolution of a paclitaxel-albumin complex. Blood samples are taken atpredetermined intervals and the concentration of paclitaxel isdetermined by HPLC methods.

Test Solutions

A solution of paclitaxel albumin complex (1 mg/ml paclitaxel) is mixedwith an equal volume 2% solution of sodium alginate and an equivalent ofencapsulated pellet form of calcium carbonate. The suspension is wellmixed and 20 ml containing 10 mg of paclitaxel is administered into thestomach of each rabbit. The alginate will react with the releasedcalcium to form a mixed insoluble calcium alginate—alginic acid gelwhich traps the albumin-paclitaxel complex. The carbon dioxide gasreleased makes the mass of the gel float on the stomach contents. Thesize of the gelatinous mass and its property of floating give the massgastric retentive properties.

As a negative control, 10 ml of paclitaxel albumin is diluted with 10 mlwater and 20 ml is administered into the stomach of a 2.5 kg rabbit.

As a positive control, 1 mg of paclitaxel in the form of the paclitaxelalbumin complex is administered intravenously to the rabbit.

Blood Sampling

Blood is drawn from a vein in the rabbit's ear. A blood sample of 0.5 mlis taken from the rabbit prior to dosing and at 0.25, 0.5, 1, 2, 4 and 6hours in heparanized test tubes. The samples are centrifuged and theplasma frozen at −70° C. for subsequent analysis by HPLC by literaturemethods.

Results

Paclitaxel concentrations in the plasma are measured by HPLC and plottedagainst time for all three dosing regimens. The values for theindividual rabbits are averaged. The normalized AUCs are calculated foreach. The ratio of the AUC for each oral dosing method to that obtainedfrom i.v. dosing is the relative bioavailability of the drug by thatmethod. Paclitaxel administered in an aqeous solution of the paclitaxelalbumin complex has low oral bioavailability, e.g. a relativebioavailability of about 5%. The gastric retention liquid formulationhas a higher bioavailability, e.g. a relative bioavailability of ˜10%,representing a two fold improvement over non-gastric retention oraldelivery of the paclitaxel.

Having thus described the invention with reference to certain preferredembodiments, other embodiments will become apparent to one skilled inthe art from consideration of the specification and examples. It isintended that the specification, including the examples, is consideredexemplary only, with the scope and spirit of the invention beingindicated by the claims which follow.

1.-3. (Canceled)
 4. A method of inhibiting cell proliferation in a tumorof a patient by orally administering a gastric retention solid dosageform or liquid composition containing an antineoplastic agent that issusceptible to removal by the P-glycoprotein efflux pump, wherein thedosage form or liquid composition releases the antineoplastic agent inthe patient's stomach, wherein the biovailability of the antineoplasticagent is greater than the bioavailability when the antineoplastic agentis administered in a non-gastric retention solid dosage form or liquidcomposition, resulting in enhanced systemic delivery of theantineoplastic agent to the tumor.
 5. The method of claim 4 whereinbioavailability is measured by the area under a curve of bloodstreamconcentration of the antineoplastic agent versus time.
 6. The method ofclaim 4 wherein the antineoplastic agent is selected from the groupconsisting of etoposide, paclitaxel, doxorubicin and vincristine. 7.(Canceled)
 8. A solid pharmaceutical dosage form for enhanced systemicdelivery of an antineoplastic agent comprising, as an active ingredient,an antineoplastic agent wherein the antineoplastic agent is absorbablethrough the lining of the stomach, jejunum or duodenum of a patient anda gastric retention vehicle composition comprising a hydrogel, whereinthe dosage form expands upon contact with gastric fluid and whereinafter ingestion by a patient the gastric retention vehicle compositionexpands to retain the dosage form in the patient's stomach for aprolonged period of time and wherein the active ingredient issusceptible to base induced deactivation.
 9. The pharmaceutical dosageform of claim 8 wherein the antineoplastic agent is irinotecan. 10-12.(Canceled).
 13. The pharmaceutical dosage form of claim 8 wherein theantineoplastic agent is susceptible to deactivation by the Pgp effluxpump of cells of the lining of the small intestine.
 14. Thepharmaceutical dosage form of claim 13 wherein the antineoplastic agentis selected from the group consisting of etoposide, paclitaxel,doxorubicin and vincristine.
 15. The solid pharmaceutical dosage form ofclaim 14 wherein the antineoplastic agent is etoposide.
 16. A method ofinhibiting cell proliferation in a tumor of a patient afflicted withtesticular tumors by orally administering a dosage form of claim 15 tothe patient.
 17. A method of inhibiting cell proliferation in a tumor ofa patient afflicted with testicular tumors by executing a therapeuticprogram of repeated oral administration of dosage forms of claim 15 tothe patient.
 18. The method of claim 17 wherein the dosage forms containa unit dose of from about 25 to about 250 milligrams of etoposide.
 19. Amethod of inhibiting cell proliferation in a tumor of a patientafflicted with small cell lung cancer by orally administering a dosageform of claim 15 to the patient.
 20. A method of inhibiting cellproliferation in a tumor of a patient afflicted with small cell lungcancer by executing a therapeutic program of repeated oraladministration of dosage forms of claim 15 to the patient.
 21. Themethod of claim 20 wherein the dosage forms contain a unit dose of fromabout 25 to about 250 milligrams of etoposide.
 22. The solidpharmaceutical dosage form of claim 14 wherein the antineoplastic agentis paclitaxel.
 23. A method of inhibiting cell proliferation in a tumorof a patient afflicted with non-small cell lung cancer by orallyadministering a dosage form of claim 22 to the patient.
 24. A method ofinhibiting cell proliferation in a tumor of a patient afflicted withnon-small cell lung cancer by executing a therapeutic program ofrepeated oral administration of dosage forms of claim 22 to the patient.25. The method of claim 24 wherein the dosage forms contain a unit doseof from about 25 to about 250 milligrams of paclitaxel.
 26. A method ofinhibiting cell proliferation in a tumor of a patient afflicted withovarian cancer by orally administering a dosage form of claim 22 to thepatient.
 27. A method of inhibiting cell proliferation in a tumor of apatient afflicted with ovarian cancer by executing a therapeutic programof repeated oral administration of dosage forms of claim 22 to thepatient.
 28. The method of claim 27 wherein the dosage forms contain aunit dose of from about 25 to about 250 milligrams of paclitaxel.
 29. Amethod of inhibiting cell proliferation in a tumor of a patientafflicted with breast cancer by orally administering a dosage form ofclaim 22 to the patient.
 30. A method of inhibiting cell proliferationin a tumor of a patient afflicted with breast cancer by executing atherapeutic program of repeated oral administration of dosage forms ofclaim 22 to the patient.
 31. The method of claim 30 wherein the dosageforms contain a unit dose of from about 25 to about 250 milligrams ofpaclitaxel. 32.-50. (Canceled).
 51. A liquid pharmaceutical compositionfor enhanced systemic delivery of antineoplastic agents comprising, asan active ingredient, an antineoplastic agent that is capable ofabsorption through the lining of the stomach, jejunum or duodenum of apatient and a gastric retention vehicle composition comprising a gellingagent wherein after ingestion by the patient the gastric retentionvehicle composition gels or precipitates to retain the dosage form inthe patient's stomach for a period of three hours or more.
 52. Theliquid pharmaceutical composition of claim 51 wherein the gastricretention vehicle composition comprises a protein.
 53. The liquidpharmaceutical composition of claim 52 wherein the protein is selectedfrom the group consisting of serum albumin, oval albumin, casein andgelatin.
 54. The liquid pharmaceutical composition of claim 51 whereinthe gastric retention vehicle composition comprises a polysaccharide.55. The liquid pharmaceutical composition of claim 54 wherein thegastric retention vehicle composition comprises a mixture ofethylhydroxyethylcellulose and a surfactant selected from the groupconsisting of cationic surfactants or anionic surfactants that are notextensively protonated in gastric fluid.
 56. The liquid pharmaceuticalcomposition of claim 55 wherein the surfactant is selected from thegroup consisting of hexadecyltrimethylammonium chloride,tetradecylbetainate chloride and hexadecylpyridinium chloride, sodiumdodecyl sulfate, sodium dodecyl monoethyleneoxide sulfate, sodiumdodecyl sulfonate, sodium dosdecyl phosphate, sodium dodecyl phosphonateand sodium p-dodecylbenzene sulfonate.
 57. The liquid pharmaceuticalcomposition of claim 54 wherein the gastric retention vehiclecomposition comprises low methoxylated pectin and a divalent metal salt.58. The liquid pharmaceutical composition of claim 57 wherein the lowmethoxylated pectin has a 20-50 percent degree of methoxylation and a3-23% degree of amidation.
 59. The liquid pharmaceutical composition ofclaim 57 wherein the divalent metal salt is calcium carbonate.
 60. Theliquid pharmaceutical composition of claim 54 wherein the gastricretention vehicle composition comprises methylcellulose.
 61. The liquidpharmaceutical composition of claim 60 wherein the methylcellulosecomprises 5% or more of the dosage form by weight.
 62. The liquidpharmaceutical composition of claim 51 wherein the gastric retentionvehicle composition comprises a mixture of from about 0.5 weight percentsodium alginate, from about 0.5 to about 3 weight percent of a naturalpolymer selected from the group consisting of xanthan gum, carrageenanand gelatin.
 63. A method of inhibiting cell proliferation in a tumor ofa patient afflicted with meta-static carcinoma of the colon or rectum byorally administering a liquid pharmaceutical composition of claim 51wherein the antineoplastic agent is irinotecan.
 64. A method ofinhibiting cell proliferation in a tumor of a patient afflicted withmeta-static carcinoma of the colon or rectum by executing a therapeuticprogram of repeated oral administration of a liquid pharmaceuticalcomposition of claim 51 wherein the antineoplastic agent is irinotecan.65. The method of claim 64 wherein the liquid pharmaceutical compositionis administered in a unit dose of from about 20 to about 250 milligramsof irinotecan.
 66. A method of inhibiting cell proliferation in a tumorof a patient afflicted with testicular tumors by orally administering aliquid pharmaceutical composition of claim 51 wherein the antineoplasticagent is etoposide.
 67. A method of inhibiting cell proliferation in atumor of a patient afflicted with testicular tumors by executing atherapeutic program of repeated oral administration of a liquidpharmaceutical composition of claim 51 wherein the antineoplastic agentis etoposide.
 68. The method of claim 67 wherein the liquidpharmaceutical composition is administered in a unit dose of from about25 to about 250 milligrams of etoposide.
 69. A method of inhibiting cellproliferation in a tumor of a patient afflicted with small cell lungcancer by orally administering a liquid pharmaceutical composition ofclaim 51 wherein the antineoplastic agent is etoposide.
 70. A method ofinhibiting cell proliferation in a tumor of a patient afflicted withsmall cell lung cancer by executing a therapeutic program of repeatedoral administration of a liquid pharmaceutical composition of claim 51wherein the antineoplastic agent is etoposide.
 71. The method of claim70 wherein the liquid pharmaceutical composition is administered in aunit dose of from about 25 to about 250 milligrams of etoposide.
 72. Amethod of inhibiting cell proliferation in a tumor of a patientafflicted with ovarian cancer by orally administering a liquidpharmaceutical composition of claim 51 wherein the antineoplastic agentis paclitaxel.
 73. A method of inhibiting cell proliferation in a tumorof a patient afflicted with ovarian cancer by executing a therapeuticprogram of repeated oral administration of a liquid pharmaceuticalcomposition of claim 51 wherein the antineoplastic agent is paclitaxel.74. The method of claim 73 wherein the liquid pharmaceutical compositionis administered in a unit dose of from about 25 to about 250 milligramsof paclitaxel.
 75. A method of inhibiting cell proliferation in a tumorof a patient afflicted with breast cancer by orally administering aliquid pharmaceutical composition of claim 51 wherein the antineoplasticagent is paclitaxel.
 76. A method of inhibiting cell proliferation in atumor of a patient afflicted with breast cancer by executing atherapeutic program of repeated oral administration of a liquidpharmaceutical composition of claim 51 wherein the antineoplastic agentis paclitaxel.
 77. The method of claim 76 wherein the liquidpharmaceutical composition is administered in a unit dose of from about25 to about 250 milligrams of paclitaxel.
 78. A method of inhibitingcell proliferation in a tumor of a patient afflicted with non-small celllung cancer by orally administering a liquid pharmaceutical compositionof claim 51 wherein the antineoplastic agent is paclitaxel.
 79. A methodof inhibiting cell proliferation in a tumor of a patient afflicted withnon-small cell lung cancer by executing a therapeutic program ofrepeated oral administration of a liquid pharmaceutical composition ofclaim 51 wherein the antineoplastic agent is paclitaxel.